High dose interleukin 2 (IL-2) is an approved regimen for metastatic renal cell carcinoma (RCC). Unfortunately, the response rate is modest and only few patients achieve durable remission. Treatments aimed to enhance the antitumor effect of IL-2 are needed. Histone deacetylase (HDAC) inhibitors represent a novel class of agents with antitumor activity by both transcriptional and non- transcriptional gene regulation. SNDX-275, a benzamide HDAC inhibitor, has been shown to have antitumor activity in preclinical models including RCC and is currently in clinical development. Our preliminary results have shown that SNDX-275 synergizes with high dose IL-2 in a murine model of RCC and the treatment was associated with reduction of regulatory T cells in tumor regional lymph nodes. The principal objective of the proposed research is to determine the therapeutic potential of modulating immune response with novel combination strategies involving HDAC inhibitors for the treatment of RCC. Our central hypotheses are that 1) targeting HDAC has shown preclinical and clinical activity in RCC;2) HDAC inhibitors have immunomodulatory properties by regulating specific subsets of T lymphocytes;and 3) there is a need to implement immunotherapies for RCC. To this end we will pursue the following goals: 1) to define the role of HDAC inhibitor in regulating specific immune cells in patients with RCC;2) to determine whether the successful combination of an HDAC inhibitor and IL-2 in a mouse model translates into clinical benefit for RCC patients. We will conduct a phase I/II study with SNDX-275 in combination with high dose IL-2 in patients with advanced clear cell RCC. This study represents a collaborative effort. It is an investigator initiated, Cancer Therapy and Evaluation Program sponsored study where the clinical aspects are supported by the Johns Hopkins U01 grant. We propose to test our central hypotheses by pursuing the following Specific Aims: Specific Aim #1: To assess the biological effects of SNDX-275 and IL-2 on immune cells in RCC patients. Specific Aim #2: To assess predictors of clinical response with the combination of SNDX-275 and IL-2. These studies are significant because they represent the development of a rational combination of HDAC inhibitors by exploiting their potential regulation of the immune system. We expect that these studies will provide 1) early clinical evidence that combining HDAC inhibitors and immunomodulators increases the antitumor effects, 2) insight on the role of HDACs in the modulations of specific T lymphocyte subtypes, and 3) the foundation for future clinical trials in RCC and other immunogenic tumors. PUBLIC HEALTH RELEVANCE: Our group is interested in the development of rational combination therapies for patients with urological malignancies with the long-term goal of testing these combinations in phase II-III clinical studies. This proposal is relevant because it will advance our understanding of the antitumor effect of a novel class of therapeutic agents, the histone deacetylase inhibitors, and help to design rational combinations to be tested in clinical trials for the treatment of kidney cancer and other solid tumors.